Preparation of n-(2-alkylthioethyl) nitroimidazoles

ABSTRACT

Alkylation of 2-alkyl-5-nitroimidazole with 2-alkylthioethanols in the presence of a hydrogen halide and Lewis acid in a reaction-inert solvent at 70*-120* C.

United States Patent Scollick et al. 1 Sept. 5, 1972 [54] PREPARATION OFN-(2- [58] Field of Search ..260/309, 251

ALKYLTHIOETHYL) NITROIMIDAZOLES rences Cited [72] Inventors: NeilMontgomery Scollick, New UNITED STATES PATENTS London, Conn. EricFrederick James Thorpe, Birchington, 3,349,096 10/1967 Rooney ..26O/ 3O9England Primary ExaminerJohn 11- Randolph [73] Assignee: Pfizer Inc.,New York, N.Y. Assistant Ex minerH rry I. Moatz Filed: Dec. 1970AttorneyConnolly and Hut; I 21 Appl. No.1 98,212 7] AB TRA Alkylation of2-alkyl-5-nitroimidazole with 2-111- 30 F A H m Data kylthioethanols inthe presence of a hydrogen halide orelgn pp ca [on on y and Lewis acidin a reaction-inert solvent at 70-120 Dec. 17, 1969 Great Britain..61,4l5/69 C.

[52] us. Cl ..260/309 6 Chin, Drawings Int. Cl. ..C07d 63/12 PREPARATIONOF N-(Z-ALKYLTHIOETHYL) NITROIMIDAZOLES BACKGROUND OF THE INVENTIONContinuing efforts to discover new, highly potent and nontoxicantiprotozoal agents have led to the discovery by Miller, et al.,Antimicrob. Agents Chemther., 1969, p. 257, of a series ofl-alkylsulfonylethyl-2-methyl-5- nitroimidazoles, prepared by oxidationof the corresponding sulfides. This invention relates to a novelsynthetic procedure, and more particularly, to a process for theproduction of l-(2-alkylthioethyl)-2- methyl-S-nitroimidazoles, usefulas intermediates in the preparation of the aforesaid antiprotozoalagents.

A number of methods in the art are useful for the alkylation ofimidazoles, one of which is the treatment of a basic solution of theimiazole with a compound that contains a functional group that iscapable of undergoing a nucleophilic displacement (Eq. 1). This group,X,

I II (1) generally being tosylate cm-Gm?) or one of the halogens. Withthis method no problems arise with 2-substituted imidazoles (I) for theanion formed (II) on treatment with base, and its tautomer areindistinguishable. Hence both give the same product after nucleophilic 9N N U U II III displacement on R'X (Eq. 1). However, if the imidazolering is also substituted in the 4 or 5 position (IV) then treatment witha base leads to two tautomers (V, VI), which are distinguishable fromeach other.

Thus N-substitution via nucleophilic attack by the imidazole anion leadsto a mixture of products( Eq. 4, 5). The ratio of the isomers VII andVIII,

N v R'X J- Y R v11 of course, depends on which tautomer V or Vl is morestrongly nucleophilic, which in turn depends on the electronegativity ofthe Y substituent in the 4- or 5- 0 position. In the case at hand, Y isthe strongly electronegative nitro group, which reduces thenucleophilicity of imidazole in general. The proximity of this group tothe negative charge in tautomer removes the charge to such a degree byinduction that essentially all nucleophilic attach occurs throughtautomer Vl (Eq. 5). As a result, the products isolatedare.l,2-disubstituted-4-nitroimidazoles, Ridd, et al., J. Chem. Soc.,1960, 1352, 1357, 1363. It has been reported, British Pat. No. 837,838;C. A., 54, 24804 (1960), that on treatment with dialkyl sulfates (IX)5-nitroimidazoles will yield l-alkyl-S-nitroimidazoles (X). Sulfateswith chains up to C (n-pentyl) have been exemplified.

IX X

Ridd and Grimison, Chem, & Ind., (1956) 983, have reported thatalkylation of 5(4)-nitroimidazole with dimethyl sulfate preferentiallygives the l-methyl-S- nitro isomer if the alkylation is carried out inaqueous formic acid.

Rooney, U. S. Pat. No. 3,349,096, has disclosed a process for thepreparation of l-hydroxyethyl-2-aryl-5- nitroimidazoles by alkylation ofthe substituted nitroimidazole with an epoxide in the presence of aLewis acid.

Alkylation of 2-methyl-5-nitroimidazole with B- bromoethyl ethyl sulfidein the presence of acetic acid is reported by Miller, et al., J. Med.Chem, l3, 849 1970) to give a 33 percent yield of the correspondingethyl 2( bt-methyl-S-nitrol -imidazolyl )ethyl sulfide.

The process of the present invention precludes the necessity for thepreparation of an alkylating species, such as the halides or sulfonateesters of the alkylthioethanols; thereby reducing the cost ofpreparation of the final product. Further, attempts to prepare saidsulfonates have been without'success. Alkylation of2-alkyl-5-nitroimidazoles employing alkylthioalkyl halides not onlyrequire preparation of highly toxic vesicants related to the mustardgases, but produce the desired alkylated imidazoles in yields inferiorto those of the present process.

SUMMARY OF THE INVENTION It has now been found that alkylation of2-alkyl-5- nitroimidazoles with alkylthioethanols in the presence of thehydrogen halide, hydrogen chloride or hydrogen bromide and a Lewis acidselected from the group consisting of AlCl ZnCl FeCl SnCh, TiCl.,, SbC1and BE, in a reaction-inert solvent at temperatures of 120 C. proceedsreadily and permits the synthesis of imidazoles of the formula:

l CHzCHrSR DETAILED DESCRIPTION OF THE INVENTION The herein describedreaction is conveniently carried out between a 2-alkyl-5-nitroimidazoleand an alkylthioethanol in a molar ratio of 1:1. It is, at times,advantageous to use a -20 percent excess of the imidazole and as much asa 100-150 percent excess can be employed. The molar ratio of hydrogenhalide and Lewis acid to the alkylthioethanol is approximately 1:1 withslight excesses of lO-25 percent of the former reagents providingoptimum results. The order of addition is not critical; in practice, theimidazole, Lewis acid and alkylthioethanol are added, either separatelyor combined, to a reaction-inert solvent containing the hydrogen halide.The solvent per se is not an integral part of the herein describedinvention, but provides a single contact phase for the startingreagents.

By reaction-inert solvent is meant a solvent which, under the conditionsof the process, does not enter into appreciable reaction with either theproducts or the reactants. Suitable solvents for the process of thisinvention include di-(lower)alkylketones, N,N-dilower)alkyl substitutedderivatives of lower alkyl carboxamides, e.g., dimethylformamide, loweralkyl nitriles, nitro(lower)alkanes and nitrobenzene. The preferredsolvent of the instant process invention is methyl isobutyl ketone, saidsolvent being an inexpensive commercial product, having goodsolubilizing characteristics for the starting reagents and products ofthe present process invention and a boiling point within the preferredtemperature range.

The reaction can be conducted over a wide tempera ture range;temperatures of from 70-120 C. are, however, preferred since thereaction' is completed in a reasonable period of time without extensivedecomposition of the starting reagents or final products. Reaction timeis not critical and depends on concentration, temperature and reactivityof the starting reagents.

The nitroimidazole products of the present invention are isolated byconventional methods known to those skilled in the art. Experimentally,the reaction mixture is cooled, diluted with water and rendered basic bythe addition of an inorganic base. The desired product can then beseparated from the inorganic hydroxide, arising from hydrolysis oftheLewis acid, by extraction with a suitable water-immiscible solvent.In instances wherein ;the original reaction solvent is water-immisciblethe product in the organic phase. When zinc chloride is employed as theLewis acid it is preferred that the reaction mixture be hydrolyzed withammonium chlorideammonium hydroxide, thus preventing the formation of aninsoluble zinc salt. An aqueous solution of sodium hydroxide is employedfor the hydrolysis of the remaining Lewis acids, sufficient base beingadded to dissolve the inorganic hydroxide resulting from Lewis acid.

The requisite 2-alkyl-5-nitroimidazoles employed as the startingreagents in the process are either commercial chemicals or are easilyprepared by one skilled in the art, e.g., by nitration of the2-alkylimidazoles according to the method of Cosar, et al., Ann. Inst.Pasteur, 96, 238 (1959) as reported by Butler,*et al., J. Med. Chem 10,891 (1967). The appropriate 2-alkylimidazoles are all known compoundspreviously reported in the chemical literature.

Alkylthioethanols, the second starting reagent for the process of theinstant invention, too, are all known in the literature and are preparedby the methods out-- lined by Reid, Organic Chemistry of BivalentSulphur, Vol. I, Chemical Publishing Co., New York, New York, 1958, p.378.

The remaining reagents, including the Lewis acids, solvents and hydrogenhalides are commercial chemicals.

As previously mentioned, the products of the process of this inventionare extremely useful in the synthesis of antiprotozoal agents. Ofparticular interest are the process products ethyl[2-(2-methyl-5-nitro-limidazolyl)ethyl]sulfide and isopropyl[2-(2-methyl-5-nitro-l-imidaZolyl)ethyl]-sulfide.

The basic products of the present process invention are converted to theacid addition salts by interaction of the base with an acid either in anaqueous or nonaqueous medium. In a similar manner, treatment of the acidaddition salts with an aqueous base solution, e.g., alkali metalhydroxides, alkali metal carbonates and alkali metal bicarbonates orwith a metal cation which forms an insoluble precipitate with the acidanion, results in a regeneration of the free base form. Such conversionsare best carried out as rapidly as possible and under temperatureconditions and method dictated by the stability of said basic products.The bases thus regenerated may be reconverted to the same or a differentacid addition salt.

The following examples are provided solely for the purpose ofillustration and are not to be construed as limitations of thisinvention, many variations of which are possible without departing fromthe spirit or scope thereof.

EXAMPLE I Ethyl[ 2-( 2-methyl-5-nitro- 1 -imidazolyl )ethyl lsulfideHydrogen chloride is passed slowly into methyl isobutyl ketone (150 ml.)contained in a 500 ml. threenecked flask until 8.03 g. has beenintroduced. 2- Methyl-S-nitroimidazole (38.1 g.; 0.3 mole), anhydrouszinc chloride (40.8 g.; 0.3 mole) and Z-hydroxyethyl ethyl sulfide (21.1g.; 0.2 mole) are then in troduced with stirring. The stirred suspension(now at 60 C. owing to heat produced during the addition) is heated toC. and kept at that temperature for 3 hours.

The reaction mixture is cooled to 20 C. and added to a well stirredsolution of ammonium chloride (27.2 g.) in water ml.), and the pH of themixture thus methylene chloride 50 ml.) and left overnight. Afterremoval by filtration of a small amount of unchanged 2-methyl-S-nitroimidazole, the solution is evaporated under reducedpressure to obtain 34.0 g. (70 percent yield) of crudeethyll2-(2-methyl-5-nitro-1- imidazolyl)ethyl]-sulfide.

The crude material is used directly in subsequent oxidation reactionswithout further purification.

EXAMPLE ll Methyl[2-(2-methyl-5-nitro-1-imida.zolyl)ethyl]sulfideHydrogen chloride is passed slowly into 150 ml. of methyl isobutylketone until 8.0 g. has been introduced. 2-Methyl-5-nitroimidazole (38.1g.; 0.3 mole), anhydrous zinc chloride (34.0 g.; 0.25 mole) and 2-hydroxyethyl methyl sulfide (18.4 g.; 0.20 mole) are then introducedwith stirring. The stirred suspension is heated to 90 C. and kept atthis temperature for 2.5 hours. The reaction mixture is cooled to C. andthe two phase product added to a well stirred solution of ammoniumchloride (34 g.) in water( 150 ml.) and the pH of the mixture thusformed is adjusted to 8.0 by the addition of dilute ammonium hydroxide.

After stirring for half an hour, the precipitated unchanged2-methyl-5-nitroimidazole is filtered off and the organic phase isseparated from the filtrate. The solvent phase is briefly washed withaqueous ammonium chloride buffer solution (pH 8.0) and the methylisobutyl ketone is then distilled off under reduced pressure to give23.3 g. of crude methyl[2-(2-methyl-5- nitro-l-imidazolyl)ethyl]sulfide(58 percent yield) as a waxy solid, m.p. 42-46 C.

The crude sulfide (10 g.) is dissolved in ethyl acetate 100 ml.) and tothe clear solution is added toluene psulfonic acid monohydrate (10 g.)in ml. industrial ethanol. An insoluble material slowly separates andprecipitation is completed by placing the suspension in the refrigeratorfor 24 hours. Filtration and drying in vacuo at C. yields 10.1 g.colorless toluene p-sulfonate (melting point 132-5 C.).

Anal. Calcd. for C H N O S-C H O S: C, 45.0; H, 5.1; N, 11.3;S, 17.1.

Found: C, 45.3; H, 5.2; N, 10.9, S, 17.3.

EXAMPLE llI N-Propyl 2-( 2-methyl-5 -nitro-1-imidazolyl)ethyl ]sulfideHydrogen chloride is passed slowly into methyl isobutyl ketone (750 ml.)until 40 g. has been introduced. 2-Methyl-5-nitroimidazole (190 g.; 1.5moles) anhydrous zinc chloride (170 g.; 1.25 moles) and 2-hydroxyethyln-propyl sulfide (120 g.; 1.0 mole) are then introduced with stirring.The stirred suspension is heated to 90 C. and kept at this temperaturefor 2.5 hours. The reaction mixture is cooled to 20 C., the

homogenous solution added to a well stirred solution of ammoniumchloride (170 g.) in water 750 ml.) and the pH of the mixture thusformed is adjusted to 8.0 by the addition of dilute ammonium hydroxidesolution. After stirring for 30 minutes, the precipitated 2-methyl-5-nitroimidazole is filtered off and the organic phase is separated fromthe filtrate. The solvent phase is briefly washed with aqueous ammoniumchloride buffer solution (pH 8.0) and methyl isobutyl ketone isdistilled off under reduced pressure. The residual brown oil is cooled,diluted with methylene chloride 200 ml.) and left overnight.

Unchanged Z-methyI-S-nitroimidazole (-6 g.) is filtered off and thesolution evaporated under reduced pressure to obtain cruden-propyl[2-(2-methyl-5-nitro- 1imidazolyl)ethyl]sulfide( 240 g.) as abrown oil.

Preparation of the toluene-p-sulfonate from 10 g. of crude product iscarried out as previously described to give 8.7 g. ofproduct, m.p.114-115 C.

Anal. Calcd. for C H N SO 'C H SO C, 47.88; H, 5.78;N, 10.47; S, 15.95.

Found: C, 48.40; H, 5.97; N, 10.14; S, 15.94.

EXAMPLE IV Ethyl 2-( 2-isopropy1-5-nitrol -imidazolyl )ethyl ]sulfideHydrogen chloride is passed slowly into methyl isobutyl ketone (68 ml.)until 3.6 g. has been introduced. 2-lsopropy1-5-nitroimidazole (10.2 g.;0.066 mole), anhydrous zinc chloride 15.3. g.; 0.11 mole) and2-hydroxyethy1 ethyl sulfide (9.5 g.; 0.09 mole) are then introducedwith stirring. The stirred suspension is heated to 90 C. and kept atthis temperature for 2.5 hours. The reaction mixture is cooled to 20 C.and added to a well stirred solution of ammonium chloride (15.3 g.) inwater (70 ml.) and the pH of the mixture thus formed is adjusted to 8.0by the addition of dilute ammonium hydroxide solution.

After stirring for half an hour the two phases are separated. Thesolvent phase is briefly washed with aqueous ammonium chloride solution(pH 8.0) and the methyl isobutyl ketone is then distilled off in vacuo.The residual brown oil containing suspended matter is diluted with anapproximately equal volume of ethyl acetate and filtered to recoverunchanged 2-isopropyl- 5-nitroimidazole (4 g.). Removal of the ethylacetate yields an oil (8.3 g.) still containing suspended solids.

Gas-liquid chromatography analysis shows the crude product to be 58percent of the desired ethyl[2-(2-isopropyl-5-nitroimidazo1yl)ethyl]sulfide which can be oxidized withoutfurther purification to the corresponding sulfone in good yield.

EXAMPLE V lsopropyl[2-(2-methyl-5-nitro-l-imidazolyl)ethyl]- sulfidehydrochloride Hydrogen chloride is slowly passed into dimethylformamideml.) until 3.6 g. has been introduced. 2- Methyl-S-nitroimidazole (8.4g.; 0.066 mole), anhydrous aluminum chloride 14.6 g.; 0.1 1 mole) and 2-hydroxyethyl isopropyl sulfide (12.0 g.; 0.1 mole) are then introducedwith stirring. The suspension is heated to C. and maintained at thistemperature for 2 hours.

The reaction mixture is then cooled, diluted with water and madestrongly basic by the addition of 'aqueous sodium hydroxide solution.The product is extracted into benzene and the organic layer separated,dried over anhydrous sodium sulfate and treated with sufficient gaseoushydrogen chloride to precipitate the hydrochloride salt of the desiredproduct, which is collected by filtration.

The product is oxidized directly without further purification.

EXAMPLE v1 Starting with the appropriate nitroimidazole andalkylthioethanol, and repeating the procedure of Exam.- ple V, thefollowing compounds are produced employin g the listed hydrogen halideand Lewis acid:

imidazolyhethyl lsulfide The above products are oxidized to thecorresponding sulfone by the procedure outlined in Example VIII.

EXAMPLE VII Methyl[ 2-( Z-methyl-S-nitrol -imidazolyl)ethyl]-sulfideoxalate To g. of methyl[2-( Z-methyI-S-nitro-limidazolyl)ethyl]sulfidetosylate, prepared in Example ll, dissolved in 75 ml. of water is addedsufficient aqueous 6N sodium hydroxide solution to provide a pH of 8.The free base is extracted (2 X 100 ml.) with ethyl acetate and theorganic phase separated and dried over anhydrous sodium sulfate. Thesolvent is concentrated to 50 ml., treated with 2.5 g. of oxalic acid inml. of ethanol and the resulting mixture cooled in a salt-ice bath. Theresulting oxalate salt is filtered and dried in vacuo.

ln a similar manner are conveniently prepared the hydrochloride,hydrobromide, nitrate, sulfate, phosphate, acetate, lactate, citrate andtartrate salts.

EXAMPLE VIII Ethyl[2-( Z-methyl-S-nitrol -irnidazolyl)ethyl]sulfone Amixture of 530 ml. of water, ethyl[2-(2-methyl-5-nitro-l-imidazolyl)ethyl]sulfide tosylate I26 g.; 0.326 mole) and 200ml. of chloroform is cooled to 7 C., and 136 ml. of 12.5 percent sodiumhypochlorite is stirred for 15 minutes, then extracted with chloroform.The combined extracts are washed with a saturated sodium bicarbonatesolution and the chloroform replaced by isopropanol. The solids arecollected and dried, 3 9 g. 48 percent yield), mp. 129-126 C.

In a similar manner are prepared the following sulmethyl 2-( 2-methyl-5-nitrol -imidazolyl )ethyl sulfone, m.p. l50151C.;

n-propyl[ 2-( 2-methyl-5-nitro- 1 -imidazolyl )ethyl ]sulfone, m.p. 9495C.

What is claimed is: I 1. In the process for preparing an imidazole ofthe formula:

AHICHISR the improvement which comprises reacting a compound of theformula:

with an alcohol of the formula:

I-IOCH CI-I SR wherein R and R are each alkyl containing from one tothree carbon atoms, in the presence of a hydrogen halide selected fromthe group consisting of hydrogen chloride and hydrogen bromide and aLewis acid selected from the group consisting of AlCl ZnCl FeCl SnClTiCl SbCl, and Bf in a reaction-inert solvent system at a temperature offrom about 70l 20 C.

2. The process of claim 1 wherein the hydrogen halide is hydrogenchloride.

3. The process of claim 2 wherein the Lewis acid is ZnCl 4. The processof claim 3 wherein the reaction-inert solvent is methyl isobutyl ketoneand the temperature is 90 C.

5. The process of claim 4 wherein R is methyl and R is ethyl.

6. The process of claim 4 wherein R is methyl and R 5 is isopropyl.

2. The process of claim 1 wherein the hydrogen halide is hydrogenchloride.
 3. The process of claim 2 wherein the Lewis acid is ZnCl2. 4.The process of claim 3 wherein the reaction-inert solvent is methylisobutyl ketone and the temperature is 90* C.
 5. The process of claim 4wherein R is methyl and R1 is ethyl.
 6. The process of claim 4 wherein Ris methyl and R1 is isopropyl.